There is a significant need for effective therapies against many types of cancers, especially carcinoma, which is often untreatable in its advanced states. Cell regulation by the Myc oncoprotein offers an attractive focus for therapeutic development. Myc is deregulated in a wide variety of cancers, including most carcinomas, through genetic and epigenetic mechanisms [M. D. Cole, Ann. Rev. Genet., 20:361-384 (1986)]. Thus, Myc-regulated mechanisms are logical targets for developing novel and broadly applicable therapeutic strategies.
Myc acts at the intersection of pathways that control cell division, differentiation, and apoptosis. In normal cells, Myc is rapidly induced following mitogenic stimulation and remains elevated throughout the cell cycle [Evan and Littlewood, Curr Opin Genet Dev. 3: 44-49 (1993)]. Induction of Myc is sufficient to drive cell proliferation [M. Eilers, et al., Nature, 340: 66-8 (1989)], while inhibition of Myc can block mitogenic signals and facilitate cell differentiation [R. Heikkila, et al., Nature, 328: 445-448 (1987); J. T. Holt, et al., Mol Cell Biol, 8: 963-973 (1988); K. D. Hanson, et al., Mol Cell Biol, 14: 5748-5755 (1994)]. Significantly, Myc can induce apoptosis [D. S. Askew, et al., Oncogene, 6: 1915-1922 (1991);.G. I. Evan, et al., Cell, 69: 119-128 (1992)], if its expression is uncoupled from the orchestration of other cell cycle regulatory events [G. I. Evan, et al., cited above]. Clinical evidence indicates that loss of the apoptotic response is associated with malignant conversion. Therefore, reactivation or derepression of this response would be desirable. Myc-activated death in epithelial cells (the precursor cell type to carcinoma) is p53-independent [D. Sakamuro, et al., Oncogene, 11: 2411-2418 (1995)], a useful feature because p53 function is often lost in carcinoma [Levine, Ann Rev Biochem, 62: 623-651 (1993)]. Thus, using Myc-activated death mechanisms is attractive, since the tumor cell could be attacked without regard to its p53 status.
Bin1 is a 451 amino acid Myc-interacting nuclear phosphoprotein [D. Sakamuro, et al., Nature Genet, 14: 69-77 (1996)], which has been implicated in the mechanism by which Myc induces apoptosis. Bin1 has several features of a tumor suppressor that is lost in breast and prostate carcinoma, where loss of apoptotic potential is tantamount to malignant conversion. First, Bin1 suppresses malignant cell transformation by Myc, but also by adenovirus E1A and by mutant p53, which act by Myc-independent mechanisms. Second, while normally ubiquitously expressed, Bin1 is frequently missing in breast and prostate carcinoma cell lines and primary tumors. Third, these deficits in expression appear to be functionally significant, because ectopic expression of Bin1 inhibits the growth of tumor cells which lack endogenous Bin1. Fourth, the N-terminal region of Bin1, termed the BAR domain, is closely related to a breast cancer-associated autoimmune antigen (amphiphysin) and a negative regulator of the yeast cell cycle (RVS167) [D. Sakamuro, et al., cited above.]. Finally, the human Bin1 gene maps to chromosome 2q14 [D. Negorev, et al., Genomics, 33: 329-331 (1996)], within a mid-2q region that is among the more frequently deleted loci in metastatic prostate cancers [M. L. Cher, et al., Canc Res, 56: 3091-3102 (1996)].
The murine and human BIN1 sequences, provided herein as FIGS. 2 and 3, are described in more detail in WO 96/34627. Of particular interest is the unique-1 (U1) region (located between aa 225-250) [D. Sakamuro et al, cited above; R. Wechsler-Reya, et al., Cancer Res, 57:3258-3263 (1997)], which mediates efficient cell growth inhibition through both Myc-dependent and Myc-independent mechanisms. U1 is encoded by exon 9 in the human Bin1 gene, located adjacent to the alternatively spliced exon 10.
There remains a need in the art for compositions and methods of regulating a deregulated Myc protein and of treating and diagnosing cancers associated with the Myc oncoprotein and/or undesirably low Bin1 levels.